MISTIE III uniquely addresses the multiple unmet needs of both patients with intracerebral hemorrhage (ICH) and the research community. ICH impacts 100,000 Americans each year. Its incidence has remained unchanged over the last century and it remains a substantial public health problem that will only grow with our aging population. Prevention programs have not changed the ICH mortality rate or the long-term functional impairment that is greater than in ischemic stroke, with disastrous personal, social and economic consequences. Only 10% of ICH subjects return to functional independence. Interventions aimed at preventing ICH growth, brain protection, and open surgical evacuation has shown little or no significant impact on this dismal outcome. Consistent with the 2005 & 2012 NINDS priorities, MISTIE III will build on MISTIE II, a Phase II proof-of-concept trial that confirmed the feasibility and safety of minimally invasive surgery for thrombolytic clot evacuation (MIS+rt-PA). MISTIE II optimized the surgical task and demonstrated a dramatic effect on ICH volume reduction. Highlighted results include clinically important improvement in good functional outcomes at both 180 days (mRS 0-3) and 365 days (mRS 0-2) (11% & 14%, respectively), with a volume reduction effect more profound than any other strategies being tested in clinical trials. This treatment, more than any other trial, specifically applies to a larger volume of cases who currently suffer the worst outcomes. These results translate into decreased cost and increased patient utility, making this innovative therapy critically important to further investigate. Additionally, this Phase II trial demonstrated that our simple training protocol produced investigational-quality surgical performance and standardized volume-reduction results with basic surgeon training that will be widely generalizable. MISTIE III will confirm the central hypothesis that minimally invasive, catheter-based clot-size reduction is associated with clinically significant functional benefits in the long-term outcome of the ICH patient. Clinically and biologically, MISTIE III is a robust pathway applicable to other multiple molecular strategies that might further mitigate injury to brain tissue. Indications point to greater local cellular surival and improved long-term recovery corresponding to the well-established tissue and animal models. The MISTIE III network can accomplish these goals with demonstrated rigor and is ready to test the critical hypotheses regarding the generalizability and effectiveness of the MIS+rtPA procedure to improve outcome after ICH. - MISTIE III: Lead Grant-Cluster Application for the Clinical Coordinating Center